0041-1337/01/7201-57/0 TRANSPLANTATION Vol. 72, 57–62, No. 1, July 15, 2001 Copyright © 2001 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. OUTCOME OF CADAVERIC RENAL TRANSPLANT PATIENTS TREATED FOR 10 YEARS WITH CYCLOSPORINE IS CHRONIC ALLOGRAFT NEPHROPATHY THE MAJOR CAUSE OF LATE GRAFT LOSS? ROBERTO MARCE ´ N, 1,2 JULIO PASCUAL, 1 JOS ´ E LUIS TERUEL, 1 JUAN JOS ´ E VILLAFRUELA, 1 MAITE ELIZABETH RIVERA, 1 FRANCISCO MAMPASO, 3 FRANCISCO JAVIER BURGOS, 4 AND JOAQUI´N ORTU ˜ NO 1 Departments of Nephrology, Pathology, and Urology, Hospital Ramo´n y Cajal, Universidad de Alcala´ , Madrid, Spain Background. The introduction of cyclosporine (CsA) has improved the short-term outcome of renal trans- plantation, but its effect on the long-term survival is not well known. Methods. We analyzed 128 cadaveric first renal transplant recipients with CsA and prednisone as basal immunosuppression followed for at least 10 years, and we have compared them with a group of 185 historical patients treated with azathioprine (Aza) and prednisone. Results. The 1-year graft survival was 83% in the CsA- treated patients and 68% in the Aza-treated patients (P<0.025), and the differences were significant for 3 years. Acute rejection accounted for the 10.9% of losses in CsA-treated patients and for 23.8% of losses in Aza- treated patients (P50.046). Chronic allograft nephropa- thy was the cause of graft losses in 40.6% and 16.8% of cases (P50.008). Patient survival at 5 years was 88% in CsA-treated patients and 79% in the Aza-treated patients (P<0.025). When analyzing the data of the 64 CsA-treated patients and the 84 Aza-treated patients with one func- tioning graft at 10 years, mean serum creatinine values were significantly higher in the CsA-treated patients at all time points but the increases were not significantly different. At 10 years, mean blood pressure was higher (P50.002), and hypercholesterolemia (P50.011) and hy- peruricemia (P50.000) were more prevalent in the CsA- treated patients. Conclusions. CsA resulted in a better short-time pa- tient and graft survival that was not maintained in the long-term outcome. Chronic allograft nephropathy was the leading cause of graft loss in CsA-treated pa- tients. Graft function was poorer in the CsA-treated patients, but its decline was similar in the two groups. The introduction of cyclosporine (CsA) in renal transplan- tation has improved the short-term graft and patient sur- vival in most studies (1–3). However, graft and patient out- comes similar to that of conventional therapy have also been reported (4). Despite CsA having been used as basic immu- nosuppression for 20 years, few studies have addressed long- term graft outcome. To the best of our knowledge, in only three studies had the patients analyzed been followed for at least 10 years, and the results were not definitive (5–7). In the European Multicentre Study (5) and in the data from Basel (6), graft survival was slightly better in patients allo- cated to CsA than in those on conventional therapy. There were no differences between the two groups when only grafts surviving more than 1 year were analyzed (5). In both stud- ies, approximately 40% of patients were switched to azathio- prine (Aza) and steroids. An important observation was that the survival curves were slowly losing the superiority of the CsA group between years 5 and 10. Ponticelli et al. (7) per- formed a randomized study in which the majority of patients were on CsA at the end of follow-up and found more marked differences: 56% graft survival at 10 years in the CsA group and 35% in the Aza group. But there was a reduction in the difference of graft survival of approximately 10% between years 5 and 10; thereafter, the number of cases included in each group is small. Other studies have shown similar rates of long-term graft attrition in patients on CsA than in pa- tients on conventional therapy (8). Because high doses of CsA may cause irreversible renal failure in patients with nonrenal diseases (9), there has been a lot concern regarding its long-term nephrotoxicity in kidney transplantation. To avoid this complication, elective with- drawal of the drug has been postulated. In several studies, including a meta-analysis (10 –12), the discontinuation of CsA increased the incidence of acute rejection, but it did not affect short-term graft or patient survival. Irreversible acute rejection episodes and death in a significant percentage of patients have also been reported (10). On the other hand, renal function measurements by serum creatinine, 1/Cr, the reciprocal of serum creatinine, or glomerular filtration rate (GFR), although reduced in patients on continuous CsA in comparison with those on conventional therapy, may remain stable in the long-term follow-up (5–8, 13–20). These findings have been taken as an argument against the progressive deterioration in renal function due to CsA nephrotoxicity. As a result of these considerations, the present study was performed (a) to analyze graft and patient survival of our first cadaveric kidney transplants treated uninterruptedly with CsA and prednisone for 10 years, (b) to determine the clinical status of the patients and the kidney allograft func- tion, and (c) to compare these results with a historical group of kidney transplant patients treated with Aza and prednisone. 1 Servicio de Nefrologı ´a, Hospital Ramo´n y Cajal, 28034 Madrid, Espan˜ a. 2 Address correspondence to: Roberto Marce´n Letosa, Servicio de Nefrologı ´a, Hospital Ramo´n y Cajal, Ctra Colmenar Viejo Km. 9.1, 28034 Madrid, Espan˜ a. 3 Servicio de Anatomı ´a Patolo´ gica, Hospital Ramo´ n y Cajal, 28034 Madrid, Espan˜ a. 4 Servicio de Urologı ´a, Hospital Ramo´n y Cajal, 28034 Madrid, Espan˜ a. 57